Kimberly Allison

Associate Professor of Pathology at the Stanford University Medical Center

Bio

Bio

Dr. Allison specializes in breast pathology. As Director of Breast Pathology, she oversees the operations of the service, participates in multidisciplinary breast discussions on breast cancer diagnosis and treatment, and directs training of residents and the breast/GYN fellow on the service. She has a special interest in the development of high quality diagnostic standards and novel diagnostic/therapy-related tumor markers. She has published on issues in diagnostic agreement, establishing appropriate diagnostic criteria and clinical management of a variety of entities. She is a member of the CAP/ASCO HER2 Testing Guidelines Review committee with special focus on patient communication. Additional areas of interest include the immune system?s response to neoplasia and pregnancy-associated breast cancers. Dr. Allison is also a breast cancer survivor and the author of ?Red Sunshine; A Story of Strength and Inspiration from a Doctor Who Survived Stage 3 Breast Cancer.?

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Research & Scholarship

Current Research and Scholarly Interests

Dr. Allison’s clinical expertise is in breast pathology. Her research interests include how standards should be applied to breast cancer diagnostics (such as HER2 testing), the utility of molecular panel-based testing in breast cancer, and identifying the most appropriate management of specific pathologic diagnoses. She is also the author of “Red Sunshine”, a memoir about her personal experience with breast cancer, a topic which she speaks about to both patient and health care audiences.

Abstract

Current data on the pathologic diagnoses of breast biopsy after mammography can inform patients, clinicians, and researchers about important population trends.Breast Cancer Surveillance Consortium data on 4,020,140 mammograms between 1996 and 2008 were linked to 76,567 pathology specimens. Trends in diagnoses in biopsies by time and risk factors (patient age, breast density, and family history of breast cancer) were examined for screening and diagnostic mammography (performed for a breast symptom or short-interval follow-up).Of the total mammograms, 88.5% were screening and 11.5% diagnostic; 1.2% of screening and 6.8% of diagnostic mammograms were followed by biopsies. The frequency of biopsies over time was stable after screening mammograms, but increased after diagnostic mammograms. For biopsies obtained after screening, frequencies of invasive carcinoma increased over time for women ages 40-49 and 60-69, Ductal carcinoma in situ (DCIS) increased for those ages 40-69, whereas benign diagnoses decreased for all ages. No trends in pathology diagnoses were found following diagnostic mammograms. Dense breast tissue was associated with high-risk lesions and DCIS relative to nondense breast tissue. Family history of breast cancer was associated with DCIS and invasive cancer.Although the frequency of breast biopsy after screening mammography has not changed over time, the percentages of biopsies with DCIS and invasive cancer diagnoses have increased. Among biopsies following mammography, women with dense breasts or family history of breast cancer were more likely to have high-risk lesions or invasive cancer. These findings are relevant to breast cancer screening and diagnostic practices.

Abstract

A breast pathology diagnosis provides the basis for clinical treatment and management decisions; however, its accuracy is inadequately understood.To quantify the magnitude of diagnostic disagreement among pathologists compared with a consensus panel reference diagnosis and to evaluate associated patient and pathologist characteristics.Study of pathologists who interpret breast biopsies in clinical practices in 8 US states.Participants independently interpreted slides between November 2011 and May 2014 from test sets of 60 breast biopsies (240 total cases, 1 slide per case), including 23 cases of invasive breast cancer, 73 ductal carcinoma in situ (DCIS), 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia. Participants were blinded to the interpretations of other study pathologists and consensus panel members. Among the 3 consensus panel members, unanimous agreement of their independent diagnoses was 75%, and concordance with the consensus-derived reference diagnoses was 90.3%.The proportions of diagnoses overinterpreted and underinterpreted relative to the consensus-derived reference diagnoses were assessed.Sixty-five percent of invited, responding pathologists were eligible and consented to participate. Of these, 91% (N?=?115) completed the study, providing 6900 individual case diagnoses. Compared with the consensus-derived reference diagnosis, the overall concordance rate of diagnostic interpretations of participating pathologists was 75.3% (95% CI, 73.4%-77.0%; 5194 of 6900 interpretations). Among invasive carcinoma cases (663 interpretations), 96% (95% CI, 94%-97%) were concordant, and 4% (95% CI, 3%-6%) were underinterpreted; among DCIS cases (2097 interpretations), 84% (95% CI, 82%-86%) were concordant, 3% (95% CI, 2%-4%) were overinterpreted, and 13% (95% CI, 12%-15%) were underinterpreted; among atypia cases (2070 interpretations), 48% (95% CI, 44%-52%) were concordant, 17% (95% CI, 15%-21%) were overinterpreted, and 35% (95% CI, 31%-39%) were underinterpreted; and among benign cases without atypia (2070 interpretations), 87% (95% CI, 85%-89%) were concordant and 13% (95% CI, 11%-15%) were overinterpreted. Disagreement with the reference diagnosis was statistically significantly higher among biopsies from women with higher (n?=?122) vs lower (n?=?118) breast density on prior mammograms (overall concordance rate, 73% [95% CI, 71%-75%] for higher vs 77% [95% CI, 75%-80%] for lower, P?.001), and among pathologists who interpreted lower weekly case volumes (P?.001) or worked in smaller practices (P?=?.034) or nonacademic settings (P?=?.007).In this study of pathologists, in which diagnostic interpretation was based on a single breast biopsy slide, overall agreement between the individual pathologists' interpretations and the expert consensus-derived reference diagnoses was 75.3%, with the highest level of concordance for invasive carcinoma and lower levels of concordance for DCIS and atypia. Further research is needed to understand the relationship of these findings with patient management.

Abstract

Pretreatment evaluation of axillary lymph nodes (ALNs) and marking of biopsied nodes in patients with newly diagnosed breast cancer is becoming routine practice. We sought to test tattooing of biopsied ALNs with a sterile black carbon suspension (Spot?). The intraoperative success of identifying tattooed ALNs and their concordance to sentinel nodes was determined.Women with suspicious ALNs and newly diagnosed breast cancer underwent palpation and/or ultrasound-guided fine needle aspiration or core needle biopsy, followed by injection of 0.1 to 0.5 ml of Spot? ink into the cortex of ALNs and adjacent soft tissue. Group I underwent surgery first, and group II underwent neoadjuvant therapy followed by surgery. Identification of black pigment and concordance between sentinel and tattooed nodes was evaluated.Twenty-eight patients were tattooed, 16 in group I and 12 in group II. Seventeen cases had evidence of atypia or metastases, 8 (50 %) in group I and 9 (75 %) in group II. Average number of days from tattooing to surgery was 22.9 (group I) and 130 (group II). Black tattoo ink was visualized intraoperatively in all cases, except one case with microscopic black pigment only. Fourteen group I and 10 group II patients had black pigment on histological examination of ALNs. Sentinel nodes corresponded to tattooed nodes in all except one group I patient with a tattooed non-sentinel node.Tattooed nodes are visible intraoperatively, even months later. This approach obviates the need for additional localization procedures during axillary staging.

Abstract

The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC.A standardized methodology for evaluating TILs is now needed as a prerequisite for integrating this parameter in standard histopathological practice, in a research setting as well as in clinical trials. This article reviews current data on the clinical validity and utility of TILs in BC in an effort to foster better knowledge and insight in this rapidly evolving field, and to develop a standardized methodology for visual assessment on H&E sections, acknowledging the future potential of molecular/multiplexed approaches.The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies.

Abstract

Although rare, neuroendocrine carcinoma of the breast (NECB) is becoming an increasingly recognized entity. The current literature is limited to case reports and small series and therefore a comprehensive population-based analysis was conducted to investigate the clinicopathologic features and long-term outcomes associated with NECB. We included all patients in the SEER Database from 2003 to 2010 with a diagnosis of NECB. The 2012 WHO classification system was used to categorize patients based on histopathologic diagnosis: well-differentiated neuroendocrine tumors, small/oat cell or poorly differentiated neuroendocrine tumors, adenocarcinoma with neuroendocrine features (ANF), large cell neuroendocrine and carcinoid tumors. Survival analysis was performed for disease specific (DSS) and overall (OS) survival. Of the 284 cases identified, 52.1% were classified as well-differentiated, 25.7% small cell, 14.8% ANF, 4.9% large cell, and 2.5% carcinoid. In general, patients presented with advanced disease: 36.2% had positive lymph node metastases and 20.4% presented with systemic metastases. Five-year DSS rates for stage I-IV NECB were 88.1, 67.8, 60.5, and 12.4%, respectively, while five-year OS rates were 77.9, 57.3, 52.9, and 8.9%, respectively. DSS and OS were significantly different for well-differentiated neuroendocrine tumors and ANFs compared to small cell and carcinoid tumors. On univariate Cox proportional hazards regression, small cell carcinoma was significantly associated with worse DSS (OR 1.97, 95% CI 1.05-3.67) and OS (OR 2.66, 95% CI 1.49-4.72) compared to other neuroendocrine tumors. NECB is associated with advanced stage disease at presentation and an unfavorable prognosis for stage II-IV disease and small cell, large cell, and carcinoid histologic subtypes.

Abstract

Lynch syndrome (LS) is an autosomal dominant inherited disease that is associated with an increased risk for colorectal and endometrial cancer due to germline mutations in mismatch-repair (MMR) genes. Whereas primary tumors in this syndrome are widely recognized, the relative risk(s) of secondary malignancies, particularly breast cancer, in LS patients are still poorly characterized. To provide an improved assessment of these risks, MMR status was evaluated in secondary tumors from a series of patients with index tumors of known MMR status (both proficient and deficient). A total of 1252 tumors (index tumors) and all secondary malignancies were tested for MMR by immunohistochemistry (MSH2, MSH6, MLH1, PMS2) between 1992 and 2013. Tumors with MLH1/PMS2 deficiency were tested for hypermethylation or BRAF mutation, when appropriate. Of the 1252 index tumors, 162 were MMR deficient (dMMR), and, of that subset, 32 secondary tumors were identified (19.7%). In contrast, 80 secondary tumors were identified in the proficient (intact) group (7.3%). Although secondary malignancies were more common in the dMMR group (P=0.0001), there was no trend in tumor type. Specifically, breast cancer was not overly represented in the dMMR group. When secondary tumors had dMMR, they were more likely to have deficiency in MSH2/MSH6 than in MLH1/PMS2 (P=0.01). Of the patients with tumors exhibiting dMMR, women were more likely to have a dMMR secondary tumor in this series (P=0.0001); however, breast cancer was not overly represented, and our study provides no evidence that it is more frequent in LS. MSH2/MSH6 deficiency is more commonly associated with a secondary tumor compared with MLH1/PMS2 deficiency, when methylation/BRAF status is taken into account.

Abstract

To assess the laboratory policies, pathologists' clinical practice and perceptions about the value of second opinions for breast pathology cases among pathologists practising in the USA.Cross-sectional data were collected from 252 pathologists who interpret breast specimens in eight states using a web-based survey. Descriptive statistics were used to characterise findings.Most participants had >10 years of experience interpreting breast specimens (64%), were not affiliated with academic centres (73%) and were not considered experts by their peers (79%). Laboratory policies mandating second opinions varied by diagnosis: invasive cancer 65%; ductal carcinoma in situ (DCIS) 56%; atypical ductal hyperplasia 36% and other benign cases 33%. 81% obtained second opinions in the absence of policies. Participants believed they improve diagnostic accuracy (96%) and protect from malpractice suits (83%), and were easy to obtain, did not take too much time and did not make them look less adequate. The most common (60%) approach to resolving differences between the first and second opinion is to ask for a third opinion, followed by reaching a consensus.Laboratory-based second opinion policies vary for breast pathology but are most common for invasive cancer and DCIS cases. Pathologists have favourable attitudes towards second opinions, adhere to policies and obtain them even when policies are absent. Those without a formal policy may benefit from supportive clinical practices and systems that help obtain second opinions.

Abstract

Digital whole slide imaging (WSI) is an emerging technology for pathology interpretation; however, little is known about pathologists' practice patterns or perceptions regarding WSI. A national sample (N?=?252) of pathologists from New Hampshire, Vermont, Washington, Oregon, Arizona, Alaska, Maine, and Minnesota were surveyed in this cross-sectional study (2011-2013). The survey included questions on pathologists' experience, WSI practice patterns, and perceptions using a six-point Likert scale. Agreement was summarized with descriptive statistics to characterize pathologists' use and perceptions of WSI. The majority of participating pathologists were males (63%) between 40 and 59 years of age (70%) and not affiliated with an academic medical center (72%). Experience with WSI was reported by 49%. Types of use reported included CME/board exams/teaching (28%), tumor board/clinical conference (22%), archival purposes (6%), consultative diagnosis (4%), research (4%), and other uses (12%). Most respondents (79%) agreed that accurate diagnoses can be made with this technology, and that WSI is useful for obtaining a second opinion (88%). However, 78% of pathologists agreed that digital slides are too slow for routine clinical interpretation. Fifty-nine percent agreed that the benefits of WSI outweigh concerns. The respondents were equally split as to whether they would like to adopt WSI (51%) or not (49%). About half of pathologists reported experience with the WSI technology, largely for CME, licensure/board exams, and teaching. Positive perceptions regarding WSI slightly outweigh negative perceptions. Understanding practice patterns with WSI as dissemination advances may facilitate concordance of perceptions with adoption of the technology.

Abstract

In vitro models of normal mammary epithelium have correlated increased extracellular matrix (ECM) stiffness with malignant phenotypes. However, the role of increased stiffness in this transformation remains unclear because of difficulties in controlling ECM stiffness, composition and architecture independently. Here we demonstrate that interpenetrating networks of reconstituted basement membrane matrix and alginate can be used to modulate ECM stiffness independently of composition and architecture. We find that, in normal mammary epithelial cells, increasing ECM stiffness alone induces malignant phenotypes but that the effect is completely abrogated when accompanied by an increase in basement-membrane ligands. We also find that the combination of stiffness and composition is sensed through ?4 integrin, Rac1, and the PI3K pathway, and suggest a mechanism in which an increase in ECM stiffness, without an increase in basement membrane ligands, prevents normal ?6?4 integrin clustering into hemidesmosomes.

Abstract

Cancer heterogeneity, long recognized as an important clinical determinant of patient outcomes, was poorly understood at a molecular level. Genomic studies have significantly improved our understanding of heterogeneity, and have pointed to ways in which heterogeneity might be understood and defeated for therapeutic effect. Recent studies have evaluated intratumoral heterogeneity within the primary tumor, as well as heterogeneity observed between primary and metastasis. The existence of clonal heterogeneity in the primary and metastasis also affects response to therapy, since the Darwinian pressures of systemic therapy result in clonal selection for initially rare variants. Novel technologies (such as measurements of circulating tumor cells and circulating tumor DNA) may allow physicians to monitor the emergence of clonal subtypes and intervene at an early point to improve patient prognosis.

Abstract

To gain a better understanding of the reasons for diagnostic variability, with the aim of reducing the phenomenon.In preparation for a study on the interpretation of breast specimens (B-PATH), a panel of three experienced breast pathologists reviewed 336 cases to develop consensus reference diagnoses. After independent assessment, cases coded as diagnostically discordant were discussed at consensus meetings. By the use of qualitative data analysis techniques, transcripts of 16 h of consensus meetings for a subset of 201 cases were analysed. Diagnostic variability could be attributed to three overall root causes: (i) pathologist-related; (ii) diagnostic coding/study methodology-related; and (iii) specimen-related. Most pathologist-related root causes were attributable to professional differences in pathologists' opinions about whether the diagnostic criteria for a specific diagnosis were met, most frequently in cases of atypia. Diagnostic coding/study methodology-related root causes were primarily miscategorizations of descriptive text diagnoses, which led to the development of a standardized electronic diagnostic form (BPATH-Dx). Specimen-related root causes included artefacts, limited diagnostic material, and poor slide quality. After re-review and discussion, a consensus diagnosis could be assigned in all cases.Diagnostic variability is related to multiple factors, but consensus conferences, standardized electronic reporting formats and comments on suboptimal specimen quality can be used to reduce diagnostic variability.

Abstract

Little is known about the frequency of discordant diagnoses identified during research.To describe diagnostic discordance identified during research and apply a newly designed research framework for investigating discordance.Breast biopsy cases (N = 407) from registries in Vermont and New Hampshire were independently reviewed by a breast pathology expert. The following research framework was developed to assess those cases: (1) compare the expert review and study database diagnoses, (2) determine the clinical significance of diagnostic discordance, (3) identify and correct data errors and verify the existence of true diagnostic discrepancies, (4) consider the impact of borderline cases, and (5) determine the notification approach for verified disagreements.Initial overall discordance between the original diagnosis recorded in our research database and a breast pathology expert was 32.2% (131 of 407). This was reduced to less than 10% after following the 5-step research framework. Detailed review identified 12 cases (2.9%) with data errors (2 in the underlying pathology registry, 3 with incomplete slides sent for expert review, and 7 with data abstraction errors). After excluding the cases with data errors, 38 cases (9.6%) among the remaining 395 had clinically meaningful discordant diagnoses (? = 0.82; SE, 0.04; 95% confidence interval, 0.76-0.87). Among these 38 cases, 20 (53%) were considered borderline between 2 diagnoses by either the original pathologist or the expert. We elected to notify the pathology registries and facilities regarding discordant diagnoses.Understanding the types and sources of diagnostic discordance uncovered in research studies may lead to improved scientific data and better patient care.

Abstract

Purpose.-To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer. Methods.-ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing. Results.-The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations. Recommendations.-The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing.

Abstract

Diagnostic test sets are a valuable research tool that contributes importantly to the validity and reliability of studies that assess agreement in breast pathology. In order to fully understand the strengths and weaknesses of any agreement and reliability study, however, the methods should be fully reported. In this paper we provide a step-by-step description of the methods used to create four complex test sets for a study of diagnostic agreement among pathologists interpreting breast biopsy specimens. We use the newly developed Guidelines for Reporting Reliability and Agreement Studies (GRRAS) as a basis to report these methods.Breast tissue biopsies were selected from the National Cancer Institute-funded Breast Cancer Surveillance Consortium sites. We used a random sampling stratified according to woman's age (40-49 vs. ?50), parenchymal breast density (low vs. high) and interpretation of the original pathologist. A 3-member panel of expert breast pathologists first independently interpreted each case using five primary diagnostic categories (non-proliferative changes, proliferative changes without atypia, atypical ductal hyperplasia, ductal carcinoma in situ, and invasive carcinoma). When the experts did not unanimously agree on a case diagnosis a modified Delphi method was used to determine the reference standard consensus diagnosis. The final test cases were stratified and randomly assigned into one of four unique test sets.We found GRRAS recommendations to be very useful in reporting diagnostic test set development and recommend inclusion of two additional criteria: 1) characterizing the study population and 2) describing the methods for reference diagnosis, when applicable.

Abstract

Pathologists are now more than ever "diagnostic oncologists" and serve a critical role as clinical consultants on the biology of disease. In the last decade and a half, molecular information has transformed our thinking about the biologic diversity of breast cancers and redirected the way clinical treatment decisions are made. A basic understanding of the current molecular classification of breast cancers and the biologic pathways from precursors to invasive disease is key to both informing diagnostic practice and serving as clinical consultants. In addition, both single-marker and panel-based molecular tests are currently being utilized in breast cancer tissue to predict the benefit of specific therapies such as HER2-targeted biologic therapy and chemotherapy. Familiarity with the current issues involving these molecular tests as well as the pathologist's role in ensuring appropriate tissue handling, tissue selection, and results interpretation and correlation are paramount to providing optimal patient care.

Abstract

By analyzing public data sets of gene expression in human breast cancers we observed that increased levels of transcripts encoding the planar cell polarity (PCP) proteins SCRIB and VANGL1 correlate with increased risk of patient relapse. Experimentally, we found that reducing expression of SCRIB by short-hairpin RNAs (shRNAs) reduces the growth of human breast cancer cells in xenograft assays. To investigate SCRIB-associated proteins that might participate in the responses of breast cancer cells to altered levels of SCRIB, we used mass spectrometry and confocal microscopy. These studies reveal that SCRIB is present in at least two unique protein complexes: (1) a complex of SCRIB, ARHGEF, GIT and PAK (p21-activated kinase), and (2) a complex of SCRIB, NOS1AP and VANGL. Focusing on NOS1AP, we observed that NOS1AP colocalizes with both SCRIB and VANGL1 along cellular protrusions in metastatic breast cancer cells, but does not colocalize with either SCRIB or VANGL1 at cell junctions in normal breast cells. We investigated the effects of shRNA-mediated knockdown of NOS1AP and SCRIB in vitro, and found that reducing NOS1AP and SCRIB slows breast cancer cell migration and prevents the establishment of leading-trailing polarity. We also find that reduction of NOS1AP enhances anchorage-independent growth. Collectively these data point to the relevance of NOS1AP and SCRIB protein complexes in breast cancer.

Abstract

The surgical management of lobular in-situ neoplasia (LN) identified by core needle biopsy (CNB) is currently variable. Our institution has routinely excised LN on CNB since 2003, allowing for an unbiased assessment of upgrade rates.Cases of LN on CNB, including atypical lobular hyperplasia (ALH) and lobular carcinoma-in-situ (LCIS), were identified in our pathology database. CNBs with concurrent pleomorphic LCIS, ductal carcinoma-in-situ (DCIS), and invasive carcinoma were excluded. Imaging indication/modality, biopsy indication, and radiologic concordance were determined. Pathology review included scoring total foci of LN in each CNB. Upgrade rates to invasive carcinoma or DCIS at excision were calculated.A total of 106 cases of LN (73 ALH and 33 LCIS) on CNB were identified. Thirty patients had concurrent atypical ductal hyperplasia (ADH) and 76 had LN alone; 93 (88%) of the patients had available surgical follow-up (25 LN + ADH and 68 LN alone). The upgrade rate at excision was 16% (4 of 25) for LN + ADH and 4.4% (3 of 68) for LN alone. Patients with LN alone and discordant imaging, imaging for high-risk indications, or extensive LCIS (>4 foci) accounted for all the upgrades. Normal-risk patients who underwent biopsy to assess calcifications found by routine mammographic screening with LN alone did not result in upgrade.Women with a CNB diagnosis of LN for calcifications found on routine, normal-risk mammographic screening have a negligible risk of upgrade and may not require excisional biopsy. However, excisional biopsy should be offered to women undergoing imaging for other indications or with >4 foci of LN on CNB.

Abstract

Immunohistochemical markers to assist in the diagnosis and classification of hyperplastic endometrial epithelial proliferations would be of diagnostic use. To examine the possible use of PAX2 as a marker of hyperplastic endometrium, cases of normal endometrium, simple and complex hyperplasia without atypia, atypical hyperplasia, and International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrioid carcinomas were stained for PAX2. Two hundred and six endometrial samples were available for interpretation of PAX2 staining. The percentage of cases with complete PAX2 loss (0% of cells staining) increased with increasing severity of hyperplasia: 0% of normal proliferative and secretory endometrium (n=28), 17.4% of simple hyperplasia (n=23), 59.0% of complex hyperplasia (n=83), 74.1% of atypical hyperplasia (n=54), and 73.3% of FIGO grade 1 endometrioid cancers (n=15). Partial loss of PAX2 expression did occur in normal endometrium (17.9%) but in smaller proportions of tissue and was less frequent than in simple hyperplasia (47.8% with partial loss), complex hyperplasia (32.5%), atypical hyperplasia (22.2%), and FIGO grade 1 carcinomas (20.0%). Uniform PAX2 expression was rare in complex (8.4%) and atypical hyperplasia (3.7%) and carcinoma (6.7%). When evaluating loss of PAX2 in histologically normal endometrium adjacent to lesional endometrium in a given case, statistically significant differences in staining were observed for simple hyperplasia (P=0.011), complex hyperplasia (P<0.001), atypical hyperplasia (P<0.001), and FIGO grade 1 endometrioid cancer (P=0.003). In summary, PAX2 loss seems to occur early in the development of endometrial precancers and may prove useful in some settings as a diagnostic marker in determining normal endometrium from complex and atypical hyperplasia and low-grade carcinomas. However, it is not useful in distinguishing between these diagnostic categories.

Abstract

Oncotype DX(TM) is an RT-PCR-based assay used to predict chemotherapy benefit in patients with estrogen receptor (ER) positive breast cancers. We were interested if routinely available pathologic parameters could predict Oncotype DX Recurrence Scores (RS) in subsets of patients. We identified 173 breast cancers with available RSs and used 104 of these as a test set and 69 cases as a validation set. Pathologic characteristics including size, histologic type, Nottingham grade, and lymphatic invasion were recorded. Test set cases were stained for ER, progesterone receptor (PR), HER2, Ki67, CyclinD1, BCL2, D2-40, and P53. Statistical correlations with RS and regression tree analysis were performed. The validation set was subjected to analysis on the basis of grade, PR, and Ki67. In the test set, grade, PR levels and Ki67 had the strongest correlation with RS (P = 0.0002-0.0007). Regression tree analysis showed grade and PR as factors that could segregate cases into RS categories, with Ki67 adding value in certain subsets. A subset of cancers with a high likelihood of having a low RS (0-18) was identified with the following characteristics: grade 1, strong PR expression (Allred score ? 5) and Ki67 ? 10%. No cases with these characteristics had a high RS (? 31) and 73% had a low RS. Cancers highly likely to have a high RS were grade 3, low to absent PR expression (Allred score <5) and Ki67 > 10%. 80% of cases with these characteristics had a high RS and no cases had a low RS. Our validation set had similar findings in these two subsets. In conclusion, When cost and time are a consideration and the added value of Oncotype DX(TM) testing is in question, it may be reasonable to assume the results of this test in two specific subsets of breast cancers: (1) grade 1, high PR, low Ki67 cancers (low RS), and (2) grade 3, low PR, high Ki67 cancers (high RS).

Abstract

Digital pathology has the potential to dramatically alter the way pathologists work, yet little is known about pathologists' viewing behavior while interpreting digital whole slide images. While tracking pathologist eye movements when viewing digital slides may be the most direct method of capturing pathologists' viewing strategies, this technique is cumbersome and technically challenging to use in remote settings. Tracking pathologist mouse cursor movements may serve as a practical method of studying digital slide interpretation, and mouse cursor data may illuminate pathologists' viewing strategies and time expenditures in their interpretive workflow.To evaluate the utility of mouse cursor movement data, in addition to eye-tracking data, in studying pathologists' attention and viewing behavior.Pathologists (N = 7) viewed 10 digital whole slide images of breast tissue that were selected using a random stratified sampling technique to include a range of breast pathology diagnoses (benign/atypia, carcinoma in situ, and invasive breast cancer). A panel of three expert breast pathologists established a consensus diagnosis for each case using a modified Delphi approach.Participants' foveal vision was tracked using SensoMotoric Instruments RED 60 Hz eye-tracking system. Mouse cursor movement was tracked using a custom MATLAB script.Data on eye-gaze and mouse cursor position were gathered at fixed intervals and analyzed using distance comparisons and regression analyses by slide diagnosis and pathologist expertise. Pathologists' accuracy (defined as percent agreement with the expert consensus diagnoses) and efficiency (accuracy and speed) were also analyzed.Mean viewing time per slide was 75.2 seconds (SD = 38.42). Accuracy (percent agreement with expert consensus) by diagnosis type was: 83% (benign/atypia); 48% (carcinoma in situ); and 93% (invasive). Spatial coupling was close between eye-gaze and mouse cursor positions (highest frequency ?x was 4.00px (SD = 16.10), and ?y was 37.50px (SD = 28.08)). Mouse cursor position moderately predicted eye gaze patterns (Rx = 0.33 and Ry = 0.21).Data detailing mouse cursor movements may be a useful addition to future studies of pathologists' accuracy and efficiency when using digital pathology.

Abstract

In breast cancer endocrine therapy, post-therapy Ki-67 assay of biopsy material predicts recurrence-free survival but is invasive and prone to sampling error. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown an early agonist or 'flare' response to tamoxifen and estradiol, but has not been tested in response to estrogen-lowering aromatase inhibitors (AIs). We hypothesized that decreased agonistic response to AIs would result in early FDG uptake decline. We also measured early response to trastuzumab (T), another targeted agent for breast cancer with differing mechanisms of action. Our study was designed to test for an early decline in FDG uptake in response to AI or T and to examine association with Ki-67 measures of early response.Patients with any stage of newly diagnosed or recurrent breast cancer were eligible and enrolled prior to initiation (or resumption) of AI or T therapy. FDG PET and tissue biopsy were planned before and after 2 weeks of AI or T therapy, with pretreatment archival tissue permitted. Cutoffs of ?20% decline in standardized uptake value (SUV) as FDG PET early response and ?5% post-treatment expression as Ki-67 early response were defined prior to analysis.Forty-two patients enrolled, and 40 (28 AI, 12 T) completed serial FDG-PET imaging. Twenty-two patients (17 AI, 5 T) had newly diagnosed disease, and 23 (14 AI, 9 T) had metastatic disease (5 newly diagnosed). Post-treatment biopsy was performed in 25 patients (63%) and was either refused or not feasible in 15. Post-treatment biopsy yielded tumor in only 17/25 cases (14 AI, 3 T). Eleven of 14 AI patients with post-therapy tissue showed FDG PET early response, and there was 100% concordance of PET and post-therapy Ki-67 early response. For the T group, 6/12 showed an FDG PET early response, including 2/3 patients with post-therapy biopsy, all with Ki-67 >5%.Substantial changes in FDG PET SUV occurred over 2 weeks of AI therapy and were associated with low post-therapy proliferation. SUV decline was seen in response to T, but few tissue samples were available to test association with Ki-67. Our results support further investigation of FDG PET as a biomarker for early response to AI therapy.

Frequency of HER2 Heterogeneity by Fluorescence In Situ Hybridization According to CAP Expert Panel Recommendations Time for a New Look at How to Report HeterogeneityAMERICAN JOURNAL OF CLINICAL PATHOLOGYAllison, K. H., Dintzis, S. M., Schmidt, R. A.2011; 136 (6): 864-871

Abstract

In 2009, a College of American Pathologists expert panel published supplemental HER2 testing recommendations suggesting that cases with between 5% and 50% individual cells amplified by fluorescence in situ hybridization be reported as "heterogeneous for HER2 gene amplification." We examined the implications of applying these recommendations to clinical practice in 1,329 consecutive breast cancer cases. By ratio criteria, 23.2% of cases met the proposed criteria for heterogeneity, of which 81.6% were not amplified and 15.5% were equivocal by standard criteria. In contrast, the proposed criteria based on HER2 signals per cell classified only 6.5% of cases as heterogeneous, of which only 8% (7/87) were not amplified and 79% (69/87) were equivocal by standard criteria. These results show that the 2 proposed criteria sets are not equivalent and that the ratio-based definition results in large numbers of nonamplified cases being classified as heterogeneous. Further definition of optimal criteria with clinical relevance is needed before HER2 heterogeneity reporting is adopted in routine practice.

Abstract

We recently described two types of stromal response in breast cancer derived from gene expression studies of tenosynovial giant cell tumors and fibromatosis. The purpose of this study is to elucidate the basis of this stromal response--whether they are elicited by individual tumors or whether they represent an endogenous host reaction produced by the patient.Stromal signatures from patients with synchronous dual primaries were analyzed by immunohistochemistry on a tissue microarray (n = 26 pairs) to evaluate the similarity of stromal responses in different tumors within the same patient. We also characterized the extent to which the stromal signatures were conserved between stromal response to injury compared to the stromal response to carcinoma using gene expression profiling and tissue microarray immunohistochemistry.The two stromal response signatures showed divergent associations in synchronous primaries: the DTF fibroblast response is more likely to be similar in a patient with multiple breast primaries (permutation analysis P = 0.0027), whereas CSF1 macrophage response shows no significant concordance in separate tumors within a given patient. The DTF fibroblast signature showed more concordance across normal, cancer, and biopsy site samples from within a patient, than across normal, cancer, and biopsy site samples from a random group of patients, whereas the CSF1 macrophage response did not.The results suggest that the DTF fibroblast response is host-specific, whereas the CSF1 response may be tumor-elicited. Our findings provide further insight into stromal response and may facilitate the development of therapeutic strategies to target particular stromal subtypes.

Abstract

We evaluated 97 cases of review-confirmed atypical ductal hyperplasia found on stereotactic vacuum-assisted breast biopsy of suspicious calcifications. The number and size of foci of atypical ductal hyperplasia and presence of a micropapillary component were noted. In addition, we recorded if a case was considered "atypical ductal hyperplasia suspicious for ductal carcinoma in situ" using specific qualitative criteria. The upgrade rate was 20.6% (20/97) for all cases and 48% (12/25) for cases suspicious for ductal carcinoma in situ. Suspicion for ductal carcinoma in situ was found to be a strong predictor of upgrade with an odds ratio of 7.4 (P = .0003). Suspicious cases with nuclear features bordering on intermediate nuclear grade had the highest upgrade rate of 75% (6/8). Cases with ? 3 foci had significantly higher upgrade rates (28%) than those with less than 3 foci (11%), but focal atypical ductal hyperplasia did upgrade (P = .04). In conclusion, qualitative features of atypical ductal hyperplasia on core biopsy such as suspicion for ductal carcinoma in situ may help stratify patients at the highest risk for upgrade.

Abstract

BRCA1 or BRCA2 (BRCA1/2)-mutated ovarian carcinomas may originate in the fallopian tube. The authors of this report investigated alterations in BRCA1/2 tubal epithelium to define the molecular pathogenesis of these carcinomas.Tubal epithelium was evaluated from 31 BRCA1/2 mutation carriers with gynecologic carcinomas (BRCA CA), 89 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO), and 87 controls. Ki-67 expression and p53 foci (?10 of 12 consecutive staining cells) were scored by 2 investigators who were blinded to patient designations. Expression levels of p27 and p21 were evaluated within p53 foci. Loss of heterozygosity at the BRCA1/2 mutation site was evaluated in microdissected p53 foci and tubal neoplasms.Background tubal proliferation as measured by Ki-67 staining was increased in the BRCA1 RRSO group (P = .005) compared with the control group. Women who had BRCA1/2 mutations had more p53 foci identified per tubal segment than women in the control group (P = .02). Levels of p27 were decreased in 12 of 28 p53 foci from women with BRCA1 mutations and in 0 of 16 p53 foci from controls (P = .002). There was no loss of the wild type BRCA1/2 allele in 5 tested p53 foci. Tubal neoplasia lost the wild type allele in 6 of 6 foci (P = .002).The current results suggested a model of tubal carcinogenesis in women with BRCA1/2 mutations. Increased proliferation occurred globally in at-risk tubal epithelium. A mutation in the tumor protein p53 gene TP53 with clonal proliferation and loss of p27 occurred before neoplastic proliferation. Loss of the wild type BRCA1/2 allele occurred with neoplastic proliferation and before invasion.

Abstract

The purpose of this article is to determine the frequency, outcomes, and imaging features of high-risk lesions initially detected by breast MRI, including atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, and radial scar.A retrospective review of our MRI pathology database was performed to identify all lesions initially detected with MRI (January 2003 through May 2007) that underwent imaging-guided needle biopsy yielding high-risk histopathologic abnormalities. Patient age, clinical indication, MRI BI-RADS lesion features, biopsy method, and histopathologic diagnosis were recorded. The frequencies of high-risk findings at needle biopsy and rates of upgrade to malignancy at surgical excision were compared across lesion imaging features with Fisher's exact test.Four hundred eighty-two MRI-detected suspicious lesions underwent needle biopsy. High-risk histopathologic abnormalities were present in 61 (12.7%) of 482 lesions: 51 (10.6%) atypical ductal hyperplasias, six (1.2%) atypical lobular hyperplasias, three (0.6%) lobular carcinomas in situ, and one (0.2%) radial scar. Correlation between the lesion site and pathology at surgical excision was confirmed for 39 of 61 lesions. Twelve (30.8%) of those 39 lesions were upgraded to malignancy (11 atypical ductal hyperplasias and one atypical lobular hyperplasia); five (41.7%) of the 12 malignancies were invasive cancer, and seven (58.3%) were ductal carcinomas in situ. No significant lesion features predictive of subsequent upgrade to malignancy were discovered.There are no specific imaging features that predict upgrade for high-risk lesions when detected with MRI. Therefore, surgical excision is recommended because upgrade to invasive carcinoma or ductal carcinoma in situ can occur in up to 31% of cases, regardless of biopsy technique.

Abstract

Limited data exist to inform clinicians and patients as to the likelihood of long-term endometrial hyperplasia response to progestin therapy, especially for atypical hyperplasia. We evaluated women with complex and atypical endometrial hyperplasia, comparing those prescribed progestin with those not prescribed progestin.This retrospective cohort study was conducted in 1985-2005 among women aged 18-88 years at an integrated health plan in Washington State. Women were ineligible if they achieved an outcome (endometrial carcinoma, hysterectomy, or both) within 8 weeks of hyperplasia diagnosis. Exposure was progestin use for at least 14 days by duration and recency. Outcomes included rate of 1) endometrial carcinoma, 2) hysterectomy, or 3) both. Analyses performed included Kaplan-Meier, incident rate ratios, and Cox proportional hazard ratios.One thousand four hundred forty-three eligible women were identified. One thousand two hundred one had complex (n=164 no progestin) and 242 had atypical (n=62 no progestin) hyperplasia. During follow-up, a median of 5.3 years (range 8 weeks to 20.8 years), 71 women were diagnosed with endometrial carcinoma (35 complex, 36 atypia) and 323 underwent hysterectomy (216 complex, 107 atypia). Among women with complex and atypical hyperplasia, rates of endometrial carcinoma among progestin users were 3.6 and 20.5 per 1,000 woman-years, respectively (compared with women who did not use progestin, 10.8 and 101.4). Among women with complex and atypical hyperplasia, rates of hysterectomy among progestin users were 23.3 and 61.4 per 1,000 woman-years, respectively (compared with women who did not use progestin, 55.1 and 297.3).Endometrial carcinoma risk is diminished approximately threefold to fivefold in women diagnosed with complex or atypical endometrial hyperplasia and dispensed progestin; hysterectomy risk is also decreased.II.

Abstract

We were interested in determining our concordance between fluorescence in situ hybridization (FISH) and a previously validated immunohistochemical HER2 assay to identify possible reasons for discordance and to determine if all reasons for discordance were addressed by the American Society of Clinical Oncology/College of American Pathologists guidelines. We reviewed 697 cases (2004-2007) in which HER2 immunohistochemical and FISH testing were concurrently done. Overall concordance between nonequivocal immunohistochemical and FISH results was 96%. Of the 19 discordant cases, 13 (68%) were interpreted as positive immunohistochemically but negative by FISH. The primary reason for this discordance was immunohistochemical interpretation. Weak stain intensity, granular staining, and interpretation in areas of crush artifact were identified as the most common issues. Of the 6 cases interpreted as immunohistochemically negative and FISH-positive, 2 were from patients known to be receiving trastuzumab at the time of biopsy, 1 was very close to the FISH equivocal category, and 4 cases had fewer than 1.5 CEP17 signals per cell (1 patient in this group was also receiving trastuzumab). Focusing on issues with HER2 immunohistochemical interpretation can improve concordance rates for immunohistochemically positive cases, but biologic reasons may explain some discordant immunohistochemically negative cases.

Abstract

To determine if patients with fewer than three foci of atypical ductal hyperplasia (ADH) who have all of their calcifications removed after stereotactic 9- or 11-gauge vacuum-assisted breast biopsy (VABB) have a rate of upgrade to malignancy that is sufficiently low to obviate surgical excision.An institutional review board-approved, HIPAA-compliant retrospective review of 991 cases of consecutive 9- or 11-gauge stereotactic VABB performed during a 65-month period revealed 147 cases of atypia. One pathologist performed a blinded review of the results of procedures performed to assess for calcifications and confirmed ADH in 101 cases with subsequent surgical excision. Each large duct or terminal duct-lobular unit containing ADH was considered a focus and counted. Postbiopsy mammograms were reviewed to determine whether all calcifications were removed. Upgrade to malignancy was determined from excisional biopsy pathology reports. Upgrade rates as a function of both number of foci and presence or absence of residual calcifications were calculated and compared by using chi(2) tests.Upgrade to malignancy occurred in 20 (19.8%) of the 101 cases. The upgrade rate was significantly higher in cases of three or more foci of ADH (15 [28%] of 53 cases) than in cases of fewer than three foci (five [10%] of 48 cases) (P = .02). Upgrade rates were similar, regardless of whether all mammographic calcifications were removed (seven [17%] of 41 cases) or all were not removed (nine [20%] of 45 cases) (P = .77). Upgrade occurred in two (12%) of 17 cases in which there were fewer than three ADH foci and all calcifications were removed.The upgrade rate is significantly higher when ADH involves at least three foci. Surgical excision is recommended even when ADH involves fewer than three foci and all mammographic calcifications have been removed, because the upgrade rate is 12%.

Abstract

The objective of the study was to estimate the age-specific incidence of endometrial hyperplasia: simple, complex, and atypical, in order of increasing likelihood of progression to carcinoma.Women aged 18-90 years with endometrial pathology specimens (1985-2003) at a large integrated health plan were identified using automated data. Incidence rates were obtained by dividing the number of cases by the estimated number of female health plan enrollees who retained a uterus.Endometrial hyperplasia peak incidence was: simple, 142 per 100,000 woman-years, complex, 213 per 100,000 woman-years, both in the early 50s; and atypical, 56 per 100,000 woman-years in the early 60s. Age-adjusted incidence decreased over the study period, especially for atypical hyperplasia.Endometrial hyperplasia incidence without and with atypia peaks in the early postmenopausal years and in the early 60s, respectively. Given that some cases of endometrial hyperplasia likely go undiagnosed, the figures provided should be viewed as minimum estimates of the true incidence.

Abstract

Our goals were to determine the frequency and upgrade rate for atypical ductal hyperplasia (ADH) diagnosed with stereotactic 9-gauge vacuum-assisted breast biopsy and to compare the frequencies and upgrade rates of ADH between 9- and 11-gauge vacuum-assisted breast biopsy.We retrospectively reviewed the pathology results of 991 consecutive 9- or 11-gauge stereotactic vacuum-assisted breast biopsy procedures from February 2001 through June 2006 and identified lesions diagnosed as ADH. The final diagnosis after surgical excision was determined from medical records. The frequencies and upgrade rates to carcinoma were calculated for all ADH lesions and compared between 9- and 11-gauge procedures. The number of core samples was recorded and compared.One hundred forty-one of 991 (14.2%) lesions yielded a diagnosis of ADH at 9- or 11-gauge stereotactic vacuum-assisted breast biopsy. Upgrade to ductal carcinoma in situ or invasive carcinoma occurred in 26 of 123 (21.1%) patients. The frequency of ADH was 83 of 600 (13.8%) lesions for 9-gauge and 58 of 391 (14.8%) lesions for 11-gauge vacuum-assisted breast biopsy. The 9-gauge upgrade rate was 16 of 74 (21.6%) lesions compared with 10 of 49 (20.4%) lesions for 11-gauge vacuum-assisted breast biopsy. There was no significant difference between the number of core samples obtained with each device (p=0.40). Neither the frequency of ADH (p=0.66) nor the upgrade rates (p=0.87) were significantly different between 9- and 11-gauge vacuum-assisted breast biopsy.Compared with an 11-gauge vacuum-assisted breast biopsy device, the use of a larger 9-gauge vacuum-assisted breast biopsy needle does not decrease the upgrade rate of ADH. Our frequency of ADH at vacuum-assisted breast biopsy is higher than any previously reported and may reflect regional differences in the incidence of breast cancer or practice patterns of the pathologist.

Abstract

In 2003, the American Joint Committee on Cancer (AJCC) initiated the 6th edition staging criteria, including pN0(i+) and pN1mi categories for breast cancer. However, the clinical significance of these categories is debated in the literature.A prospective registry was used to identify patients staged with sentinel lymph node (SLN) biopsy. SLN evaluation included routine serial sectioning and immunohistochemical stains. SLN biopsies performed before January 2003 were restaged according to the AJCC's 6th edition criteria.Of 954 SLN biopsies identified, on review, 491 N0i-, 86 N0i+, 73 N1mi, 146 N1a, 29 N2a, and 11 N3a patients were available for analysis with a median follow-up of 45.4 months. Significant prognostic and therapeutic differences existed between the groups. Differences in overall survival (OS) and recurrence-free survival (RFS) were only noted when the size of the metastases reached the N1a level. There were no statistically significant differences in OS or RFS between N0(i-) and N0(i+) or N1mi disease. Cases that were N0(i+) or N1mi were more likely to have other poor prognostic factors and to receive more aggressive therapy.SLN biopsy allows a more sensitive evaluation of lymph nodes for metastatic cells. This has led to the increased identification of very small axillary metastases. While the new microstaging categories are not yet clearly associated with a significantly decreased OS or DFS in this series, they are associated with other poor prognostic factors and more local/regional and systemic therapy. Further analysis of the microstaging categories is needed.

Abstract

FoxP3 is a marker for immunosuppressive CD25+CD4+ regulatory T cells. These regulatory T cells are thought to play a role in inducing immune tolerance to antigens and may be selectively recruited by carcinomas. We investigated whether breast carcinomas had significant numbers of FoxP3-positive regulatory T cells by immunohistochemistry, and if their presence was associated with other prognostic factors, such as Nottingham grade, hormone receptor immunohistochemical profile, tumor size, or lymph node metastases. Ninety-seven needle core or excisional breast biopsies with invasive breast carcinoma diagnosed at the University of Washington were stained with antibodies to FoxP3, estrogen receptor, and Her2/neu. The numbers of FoxP3-positive cells present within the neoplastic epithelium, and immediately adjacent stroma were counted manually in three high-powered fields (HPFs; x 400) by two independent pathologists. The average scores were then correlated with the parameters of interest. A threshold of >or=15 FoxP3-positive cells/HPF was used to define a FoxP3-positive case in some analyses. Higher average numbers of FoxP3-positive cells present significantly correlated with higher Nottingham grade status (P=0.000229). In addition, the presence of significant numbers (>or=15/HPF) of FoxP3-positive cells in breast carcinoma was positively associated with higher Nottingham grade (P=0.00002585). Higher average numbers of FoxP3-positive cells were also significantly associated with larger tumor size (>2.0 cm; P=0.012824) and trended toward an association with estrogen receptor negativity. Interestingly, 'triple-negative' (estrogen and progesterone receptor negative and Her2/neu negative) Nottingham grade III cases were also significantly associated with high numbers of FoxP3 cells. These results argue that regulatory T cells may play a role in inducing immune tolerance to higher grade, more aggressive breast carcinomas, and are a potential therapeutic target for these cancers.

Abstract

Our goal was to determine the upgrade rate for lesions described as focal atypical ductal hyperplasia (ADH) after 9- or 11-gauge stereotactic vacuum-assisted breast biopsy (VABB) to determine whether surgical excision is indicated in this setting.We retrospectively reviewed the results of 991 consecutive 9- or 11-gauge stereotactic core VABB procedures from February 2001 through June 2006 and identified lesions diagnosed as ADH. On the basis of the descriptions in pathology reports each lesion was placed in one of three categories: (1) focal ADH, (2) ADH suspicious for ductal carcinoma-in-situ, or (3) ADH not otherwise specified. The final diagnosis after surgical excisional biopsy was determined from medical records. The frequencies and upgrade rates to carcinoma were calculated and compared for all lesions and for each ADH category.A total of 141 (14.2%) of 991 lesions yielded ADH at stereotactic core VABB, and 123 (87.2%) of 141 underwent surgical excisional biopsy of the stereotactic core VABB site. A total of 56 (45.5%) of 123 were categorized as focal ADH, and 7 (12.5%) of 56 were upgraded to carcinoma. A total of 49 (39.8%) of 123 were categorized as ADH not otherwise specified, and 11 (22.4%) of 49 were upgraded. Eighteen (14.6%) of 123 were categorized as suspicious for ductal carcinoma-in-situ, and 8 (44.4%) of 18 were upgraded. Neither the frequency of ADH (P = .66) nor the upgrade rates (P = .87) were significantly different between 9- and 11-gauge VABB.Surgical excisional biopsy is indicated to exclude carcinoma in cases of focal ADH discovered at 9- or 11-gauge VABB.

Abstract

Despite advances in defining the biology of endometrial carcinomas, there has been little progress in determining markers that distinguish preinvasive endometrial proliferations. The goal of this literature review was to identify studies on endometrial hyperplasia (EH) that describe markers with potential to predict response to progestin therapy or potential for progression to invasive disease.Articles published between January 2000 and October 2006 were identified using the key words endometrial hyperplasia and progesterone receptor or estrogen receptor or biologic marker or immunohistochemistry/immunohistochemical. Articles that reported immunohistochemical studies on specimens of human EH +/-endometrioid endometrial carcinoma with a normal comparison group were included. Only those who reported hyperplasia with atypia separately from nonatypical hyperplasia and with a sample size greater than 10 specimens for the sum of complex and atypical samples were included.A total of 289 abstracts were reviewed and 150 articles potentially met inclusion criteria. Of these, 123 described immunohistochemical studies on human EH specimens. Only 46 met all criteria for analysis of 61 different markers.PTEN seems to have the greatest potential for diagnostic utility in EH, perhaps in combination with Bcl-2 and Bax. However, more uniform and rigorous studies are required to confirm these and additional markers' utility diagnostically in a diagnostic panel. As a major clinical priority is to determine which lesions can be treated medically and which require surgical intervention, focusing future studies on markers that distinguish response to hormone therapy or are involved in hormone regulation, will be important future considerations.

Abstract

Forty percent of women with ovarian cancer have circulating free tumor DNA. We sought to determine if the tumor immune infiltrate varied based on tumor p53 mutation status or presence of circulating tumor DNA.We performed immunohistochemistry on 119 ovarian cancer specimens with CD3 and CD8 (Intratumoral T cells (TILs)), CD68 (tumor-associated macrophages (TAMs)), and FoxP3 (T regulatory cells (Tregs)). Tumors had been previously sequenced for mutations in exons 4-10 of p53, and plasma from women characterized for free tumor DNA.TIL and TAM levels were positively correlated (P<0.0001). High levels of TILs were identified in 54 of 119 tumors (45.4%). No survival difference was identified according to the presence of TILs or TAMs. Patients with greater TILs were more likely to be optimally cytoreduced (P=0.005). p53 mutations were associated with more TILs (P=0.008). The presence of circulating tumor DNA did not correlate with TILs, TAMs, or Tregs. In the subgroup with a low host antitumor immune response, the intermediate response Tregs group did have a survival advantage (P=0.049).p53 mutations are associated with higher levels of TILs. The ratio of Tregs to TILS may be more important than absolute levels. A brisk T cell response within the tumor predicts adequacy of cytoreduction, suggesting successful cytoreduction may be partially due to underlying tumor biology and host response.

Abstract

Current World Health Organization classification of endometrial hyperplasia is problematic because of poor diagnostic reproducibility. We sought to determine factors that cause diagnostic disagreement in a review of 2601 endometrial specimens. Blinded random specimens of normal endometrium, hyperplasias, and carcinoma were reviewed by 2 pathologists, with review by a third pathologist in cases with disagreement. All cases of endometrial hyperplasia or carcinoma were scored for degree of glandular crowding, architectural complexity, and cytologic atypia. Sample adequacy, hyperplasia volume, presence of metaplasia, or endometrial polyp were also scored. The overall kappa for agreement was 0.71, with a lower kappa of 0.36 when cases called "no hyperplasia" were excluded. The percent specific agreement was 90.3% for no hyperplasia, 31.1% for simple hyperplasia, 51.1% for complex hyperplasia, 49.8% for atypical hyperplasia, and 57.5% for adenocarcinoma. Cases categorized as "low volume hyperplasia" had more diagnostic disagreement than "high volume," (62% vs. 39%, P=0.003). Similarly, cases called "scant" had more diagnostic disagreement than "not scant" (65% vs. 57%, P=0.013). The histologic feature associated with the most diagnostic disagreement was cytologic atypia (P<0.0001). Architectural crowding, architectural complexity, or the presence of a polyp were all associated with diagnostic disagreement (P<0.0001). High diagnostic disagreement in endometrial hyperplasia is related to both sample adequacy and interpretation of histologic features present. Although obtaining additional tissue may increase diagnostic reproducibility, differences in interpretation of key histologic features like cytologic atypia remain major factors contributing to diagnostic disagreement.

Abstract

How much borderline change in an otherwise typical ovarian serous cystadenoma should warrant classification as a serous ovarian "borderline tumor?" We correlated estimated volume and percent borderline change with stage in 56 cases of serous ovarian neoplasms (excluding carcinomas) diagnosed as at least focal borderline change to see if we could define an appropriate threshold for the diagnosis of borderline tumor that would justify full surgical staging. Forty-three cases were completely staged, 6 had "fertility-sparing" but otherwise complete staging, and 7 cases had "limited" staging. Thirty-eight cases were stage 1a-1c, and 18 were greater than stage 1. Cases with stage 1 disease had a significantly lower mean volume of borderline change sampled of 2.0 compared with 5.6 cm in cases with greater than stage 1 disease (P = 0.0002). All high-stage cases had at least 1.0 cm or more of borderline change sampled (range, 1.0-12). Cases with stage 1 disease had a significantly lower mean estimated total percent borderline change of 34.8% compared with 77.2% in cases with greater than stage 1 disease (P < 0.0001). All high-stage cases had 20% or more total borderline change (range, 20%-100%). In addition, a grossly exophytic growth pattern component was highly predictive of high stage (P < or = 0.0001). Two cases recurred-both were advanced-stage and high-percent borderline change. There were no deaths due to disease (mean follow-up, 85 months). Our study supports a conservative 10% cutoff for classification as a "borderline tumor," and that complete surgical staging is not necessary when a serous neoplasm with an intracystic growth pattern has less than 10% or 0.5-cm borderline change.

Abstract

We present a brief review of epithelioid trophoblastic tumor, a rare trophoblastic neoplasm derived from chorionic-type intermediate trophoblastic cells that typically presents in reproductive-age women between 1 and 18 years following a previous gestation. Histologic features include a nodular growth pattern of monomorphic, epithelioid cells within a hyaline matrix. Areas of necrosis and mitotic activity (0-9 mitoses per 10 high-power fields) are additional features of this neoplasm. Positive immunostaining for p63 and cytokeratin, frequent location in the lower uterine segment and endocervix, as well as the epithelioid appearance can lead to confusion with squamous cell carcinoma. Inhibin-alpha is typically expressed, as well as focal, more variable expression of other trophoblastic markers including beta-human chorionic gonadotropin, human placental lactogen, placental alkaline phosphate, and Mel-CAM (CD148). The clinical behavior of this rare form of gestational trophoblastic disease is difficult to predict. Although most cases follow a benign course following resection, there is a potential for metastatic disease.

Abstract

In breast cancer treatment, immediate completion of axillary lymph node dissection (ALND) can be performed if the intraoperative sentinel lymph node (SLN) examination is positive. This study evaluates the accuracy of intraoperative imprint cytology (IC) for detecting SLN metastases.Pathology reports from 385 SLN biopsy examinations were reviewed retrospectively. The SLNs were serially sectioned perpendicular to the long axis and IC was performed intraoperatively. The SLNs then were formalin-fixed for permanent sections. Final pathology was compared with the intraoperative IC results.The sensitivities for IC detection of N0(i+) (n = 36), N1mi (n = 24), and N1a-3a (n = 65) metastases were 0%, 4%, and 74%, respectively. The specificity was 100%.Final pathology identified 89 (23%) patients with N1 or greater disease. IC allowed 49 (55%) of these patients to undergo synchronous completion of ALND. No unnecessary completion ALNDs were performed. The sensitivity of IC decreased with decreasing size of the metastasis.

Abstract

Opiate toxicology testing is routinely performed in the hospital setting to identify abusers and/or to determine those patients who are not taking prescribed opiate analgesics such as oxycodone. Commercially available assays for opiate detection in urine have decreased sensitivity for oxycodone, which contributes to a high false-negative rate. Functioning as a beta site, our Veterans Affairs hospital evaluated a new enzyme immunoassay, DRI Oxycodone Assay, for its use in the qualitative and semiquantitative detection of oxycodone in urine. We hypothesize that an immunoassay for oxycodone with superior sensitivity and specificity, when compared to the traditional opiate assays, would reduce the need for more expensive and time-consuming confirmatory testing. We used the new liquid homogenous enzyme immunoassay to determine oxycodone results in a total of 148 urine samples from 4 different sample groups. Gas chromatography-mass spectroscopy was subsequently used to confirm the presence or absence of oxycodone (or its primary metabolite, noroxycodone). We also evaluated within-run, between-run, and linearity studies and conducted a crossover study to establish a cutoff value for oxycodone. In our patient population, we used the new DRI immunoassay to evaluate 17,069 urine samples to estimate oxycodone misuse profiles (patients not taking prescribed oxycodone or taking oxycodone without a prescription) during a 4-month period. The sensitivity and specificity of the new oxycodone immunoassay were 97.7% and 100%, respectively, at the cutoff concentration of 300 ng/mL. The assay linearity was 1,250 ng/mL, and the sensitivity was 10 ng/mL. Within-run precision and between-run coefficient of variation were 2.3% and 1.8%, respectively. None of the 15 compounds that we evaluated for interference had crossover significant enough to produce a positive oxycodone result when using 300 ng/mL as the cutoff value. None of the 17,069 oxycodone immunoassays was followed with a request for confirmation. Among patients with positive results (n = 224), 93 (41.5%) were not prescribed oxycodone. The new DRI Oxycodone Assay is a sensitive and specific screening test for the determination of oxycodone. The improved opiate screening results may lead to better patient and prescription management, to decreased laboratory spending, and to the identification of oxycodone abusers, which could result in decreased oxycodone-related mortality.

Abstract

We reviewed the clinicopathologic features of 5 cases of malignant peripheral nerve sheath tumor (MPNST) manifesting in superficial locations associated with cutaneous neurofibromas (4 cases) or superficial peripheral nerve (1 case). Four cases had spindle cell morphologic features and were at least focally positive for S-100 protein, whereas the associated benign neural elements had more extensive S-100 immunoreactivity. The single epithelioid case was diffusely and strongly positive for S-100 protein. Melanoma markers, epithelial membrane antigen, glial fibrillary acidic protein, neurofilament, pancytokeratin (AE1/AE3), CD34, smooth muscle actin, and desmin were negative in all cases. There were no local recurrences, but 3 patients died of metastatic disease within 2 to 30 months (median, 21 months). MPNSTs can occur in a superficial location and may have an aggressive clinical course. Immunohistochemical markers are helpful in excluding other lesions in the differential diagnosis. However, identification of a benign precursor or origin from a nerve may be the most definitive way to properly classify these rare lesions.

Abstract

Liver metastases usually present as radiographically detectable mass lesions that do not significantly compromise liver function. Rarely, metastatic carcinoma can diffusely infiltrate hepatic sinusoids, a pattern of metastasis that may be missed on imaging studies, and can result in liver failure.To describe the clinicopathologic features of 3 cases of diffuse intrasinusoidal hepatic metastases from primary breast carcinomas identified at autopsy.Clinical histories and radiographic, macroscopic, and microscopic appearances of the livers were compared. Sampled liver tissue was stained with antibodies to E-cadherin, smooth muscle actin, and CD44.Two of 3 cases had a history of infiltrating ductal carcinoma of the breast and presented with new-onset liver failure, but no hepatic metastases were identified on radiologic imaging. An additional case had no history of carcinoma, presented with a severe thrombocytopenic thrombotic purpura-like syndrome, and metastatic carcinoma of the breast was diagnosed only at autopsy. The livers in all 3 cases at autopsy were homogeneous, firm, and tan-yellow, and contained no large metastatic lesions. Microscopically, poorly differentiated carcinoma diffusely infiltrated hepatic sinusoids. Antibodies to smooth muscle actin stained activated hepatic stellate cells lining involved sinusoids. Cell surface adhesion molecules, E-cadherin or CD44, were not detected in any hepatic metastases.Diffuse intrasinusoidal hepatic metastases of breast carcinoma can occupy a large percentage of the hepatic volume, yet remain occult both radiographically and macroscopically. This type of metastatic spread can present as cryptogenic liver failure. The 3 cases we studied were associated with an absence of E-cadherin and CD44 expression.

Abstract

Angiosarcoma occurs very rarely in the intestinal tract as either a primary or metastatic malignancy and can present great diagnostic difficulty, especially when it displays epithelioid cytomorphology. Since only isolated case reports have been published, the purpose of this study is to more fully delineate the histopathological and clinical features from a series of 8 angiosarcomas involving the gastrointestinal tract. There were 5 male and 3 female patients whose ages ranged from 25-85 years (median 57). Presenting symptoms included intestinal bleeding, anemia and pain. Five cases involved the small bowel and 3 involved the colon/rectum. Four cases were primary to the intestinal tract, 2 patients initially presented with secondary involvement of the large bowel from occult retroperitoneal primaries, 1 patient presented with disseminated disease including small bowel involvement, and 1 case was metastatic from a breast primary. Seven cases were composed predominantly of sheets of malignant appearing epithelioid cells with subtle areas forming cleft-like spaces suggestive of vascular differentiation. Immunohistochemical studies revealed the lesional cells to be immunoreactive for CD31 (8/8), CD34 (8/8), Factor VIII (8/8), cytokeratins AE1/AE3 (7/8), cytokeratin 7 (2/8), Cam5.2/cytokeratin 8 (5/8), and cytokeratin 19 (5/8). Cytokeratin 20 was negative in all eight cases, which contrasts sharply with the characteristic positivity for cytokeratin 20 in virtually all intestinal carcinomas. One case was weakly and focally positive for EMA and all cases were negative for S-100 protein. Cytokeratin staining was variable and ranged from focal to extensive. Follow-up was available in eight cases and ranged from 1-33 months (median 12.5). Five patients died of disease, between 1 and 33 months (median 6) after diagnosis. One recently diagnosed patient is alive with disease 18 months after diagnosis, and one patient is free of disease 27 months after original diagnosis. Angiosarcomas of the gastrointestinal tract commonly display epithelioid cytomorphology, may be diffusely and strongly positive for cytokeratins and only show subtle signs of vascular differentiation, creating potential diagnostic confusion with primary or metastatic carcinoma. Given the clinically aggressive behavior of angiosarcoma, proper classification and treatment is important. Immunohistochemistry with vascular markers, CK20, and S-100 protein may be helpful in differentiating angiosarcoma from carcinoma and melanoma.

Abstract

Myelolipomas are benign tumors composed of both mature adipose and myeloid tissues. They typically present as an incidental mass in one of the adrenal glands proper. However, they can occur in ectopic adrenal tissue or, rarely, without associated adrenal tissue in various locations and can grow to weights of several kilograms. These tumors have been linked to endocrinopathies, such as Cushing disease and congenital adrenal hyperplasia, which involve overproduction of adrenocorticotropic hormone. We report a case of three giant adrenal myelolipomas arising in a persistently virilized female with congenital adrenal hyperplasia, supporting a role for hormonal stimuli in myelolipoma formation.